The objective of the proposed research is to identify the genetic and biological bases for features of the Down Syndrome (DS) phenotype. This will be accomplished through the use of large segments of human chromosome 21 (HSA21) cloned as yeast artificial chromosomes, or YACs, and introduced into the germ line of the mouse. These YAC transgenics will be analyzed for the neurobiological and other features of the DS phenotype. The Specific Aims of the project are: 1) To determine if the overexpression of the amyloid precursor protein (APP) gene in transgenic mice leads to the neuropathology seen in DS. A principal pathologic hallmark of DS is deposition of B-amyloid protein (ABeta) forming plaques in the parenchyma of amygdala, hippocampus, and neocortex. ABeta is a small peptide derived from the amyloid precursor protein, an integral membrane glycoproteins encoded by a large gene (400kb) on HSA21. Possible mechanisms involved in the production of ABeta and the formation of the amyloid-containing plaques include the overexpression of APP. We will analyze several lines of APP YAC transgenics as they age, including lines with different levels of APP overexpression, as well as line carrying a mutation in the APP gene, which in humans results in Alzheimer's disease. 2) To determine if the overexpression of superoxide dismutase 1 (SOD1) in transgenic mice results in features of DA. The overexpression of SOD1 has been reported in transgenic mice to result in abnormal neuromuscular junctions. The transgene used in those experiments did not have the regulatory sequences responsible for tissue-appropriate expression. We will repeat these studies with YAC transgenics that carry significantly more upstream sequences of the SOD1 gene. We will also examine the effects of SOD1 overexpression as a result of a mutation in the human SOD1 gene. 3) To determine if the dosage imbalance of genes on several selected YACs carrying HSA21 sequences from he 21q22 region (and more distally) results in features of DS in transgenic mice. We will select stable, nonchimeric YACs with known markers or genes and will introduce these into the germ line of mice. If features of the DS phenotype are observe in the transgenic mice, the sequence responsible will be defined through YAC fragmentation and hybridization gene cloning strategies.